Therapy for multiple myeloma (MM) remains unsatisfactory. Conventional chemotherapy, including high-dose treatment with stem cell support, prolongs survival but is essentially palliative, indicating the need for novel agents. Novel approaches directed at specific cellular molecular targets important in the proliferation of myeloma cells may improve outcome. The PI3K/Akt/mTOR pathway mediates the growth and survival of myeloma cells, and is negatively modulated by PTEN, a product of a tumor suppressor gene. PTEN may be mutated in some cases of MM, and lead to increased signaling through PI3K/Akt. We investigate the inhibition of the PI3K/Akt/mTOR pathway as a therapeutic target in MM using CCI-779, an inhibitor of mTOR, involved in downstream signaling that couples mitogenic signals with cell cycle transit. Specifically, we propose 1) to conduct a phase II trial of CCI-779 in relapsed or refractory MM patients to assess the clinical response, 2) prospectively study the frequency of PTEN mutations or gene silencing in MM, and correlate their present mutations and silencing with clinical response to CCI-779, as PTEN expression appears to influence a cell's sensitivity to the drug in vitro, and 3) correlate the in vivo pharmacodynamic activity of CCI-779 on peripheral blood mononuclear cells with that on myeloma cells, and with plasma levels of the drug in patients treated. The results of this research have important significance for the treatment of MM and may lead to a novel therapeutic approach in this disease.